JP2000136183A - Production of n-benzyl-4-formylpiperidine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce N-benzyl-4-formylpiperidine in high yield in a simple easy manner at a low cost through an industrially excellent new process by reducing an N-benzylpiperidine carboxylic acid derivative with a new reducing agent obtained from a specific compound and a cyclic amine. SOLUTION: The objective compound of formula II is obtained by reducing an N-benzylpiperidine carboxylic acid derivative of formula I (R is H, a lower alkyl or the like) (e.g. methyl N-benzylpiperidine carboxylate) with a reducing agent derived from (A) sodium bis(2-methoxyethoxy)aluminum hydride and (B) a cyclic amine (preferably, pyrrolidine). It is preferable to use 1-3 equivalents or more of the component A based on the compound of formula I, and one or more equivalents of the component B based on the component A. An alkali metal alcoholate is preferably added further to the reducing agent since this can suppress the generation of a byproduct and obtain the objective product in higher efficiency.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION N-benzyl-4-formylpiperidine is used as an important intermediate for the production of donepezil hydrochloride, which is a therapeutic drug for senile dementia and Alzheimer's disease, for example. Therefore, the present invention relates to a novel industrially excellent method for producing N-benzyl-4-formylpiperidine, which is useful as an industrial intermediate for pharmaceuticals and the like.

[0002]

2. Description of the Related Art Conventionally, N-benzyl-4-formylpiperidine has been produced mainly by the following synthesis method. (1) Reaction of N-benzyl-4-piperidone with Me ₂ S (O) = CH ₂ to give 6-benzyl-1-oxa-6-azaspiro [2.5] octane, followed by boron trifluoride ether complex To process.
(Ind.Chim.Belge, 32 , 64-5, 1967.) (2) Reaction of N-benzyl-4-piperidone and methoxymethyltriphenylphosphonium salt to form N-benzyl-4- (methoxymethylene) piperidine, Then it is hydrolyzed.
(Ind.Chim.Belge, 32 , 64-5, 1967., Example 3a of JP-A-64-79,151) (3) N-benzyl-4-piperidone and trimethylsilyldiazomethane were added to an excess amount of diisopropylamine. The reaction is carried out in the presence to the enamine and then to the aldehyde. (Synlett, 2, 109,1994.) (4) the N- benzyl piperidinecarboxylate reduction with diisobutylaluminum hydride. (Example 2 of US-5,428,043)

[0003]

[Problems to be solved by the present invention] However, Me ₂ S (O) = CH ₂ used in the method (1) is unstable and is not commercially available, so it is necessary to prepare it as needed, and industrially It was not available. The methoxymethyltriphenylphosphonium salt used in (2), for example, methoxymethyltriphenylphosphonium chloride is an excellent reagent in terms of yield and reactivity, but is expensive and has a very large molecular weight, so that a large amount of reaction residue Was not suitable as an industrial production method. Trimethylsilyldiazomethane used in (3) is commercially available as a hexane solution, but is not suitable as an industrial production method because it is extremely flammable, irritating and expensive. The diisobutylaluminum hydride used in (4) is commercially available as a toluene or THF solution, but is easily deactivated by moisture, has high ignitability and flammability, has a low yield, and has a very low temperature (-78
C), which is not suitable as an industrial production method. As described above, an industrially excellent method for producing N-benzyl-4-formylpiperidine has not been established yet, and a new excellent method has been demanded.

[0004]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
The inventors have found that the desired N-benzyl-4-formylpiperidine can be obtained in a high yield, simply, safely and inexpensively by the method described below, and have completed the present invention. Therefore, the present invention provides an industrially excellent method for producing N-benzyl-4-formylpiperidine.

Next, the present invention will be described in detail. The present invention
This is a method for producing N-benzyl-4-formylpiperidine, which is represented by the following chemical reaction formula. (In the formula, R has the same meaning as described above.)

[0006]

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Here, the cyclic amine (I) according to the present invention comprises:
It is not limited as long as it is a free form of a cyclic amine containing an NH group. Specific examples include pyrrolidine, piperidine, morpholine, and N-methylpiperazine, and they may be used alone or in a mixture. Of these, pyrrolidine gives more favorable results. In place of the cyclic amine (I),
The reaction proceeds even when a chain amine such as diethylamine is used, but there is a problem that the reaction does not stop at the target aldehyde compound but proceeds excessively to the alcohol compound.
Use of (I) gives very good results in selectivity.
(See Comparative Example 1)

Further, sodium bis (2-methoxyethoxy) aluminum hydride used as a reducing agent in the present invention is represented by the chemical formula [(CH ₃ OCH ₂ CH ₂ O) ₂ AlH ₂ ] Na [CAS registration number: 22722 -98-1], usually commercially available as a toluene solution.

Next, the N-benzylpiperidinecarboxylic acid derivative (II) according to the present invention is represented by the following general formula.

[0010]

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In the formula, R is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group. Group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group.

More specifically, the definition of R is, for example, a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, a lower halogenated alkyl group, a lower alkoxyalkyl group, a hydroxy lower alkyl group. Group, a lower alkoxycarbonylalkyl group, a cyano lower alkyl group, a nitro lower alkyl group, a lower alkylthioalkyl group, a mercapto lower alkyl group, a lower acylalkyl group, an amino lower alkyl group which may be substituted with a nitrogen atom, and a hetero atom. A group derived from a ring including, an aryl group, a lower alkylaryl group,
Lower alkoxyaryl group, halogenated aryl group, cyanoaryl group, nitroaryl group, hydroxyaryl group, mercaptoaryl group, acylaryl group, heteroaryl group, lower alkylheteroaryl group, lower alkoxyheteroaryl group, halogenated heteroaryl Group, cyanoheteroaryl group, nitroheteroaryl group, hydroxyheteroaryl group, mercaptoheteroaryl group, acylheteroaryl group, aralkyl group, lower alkylaralkyl group, lower alkoxyaralkyl group, halogenated aralkyl group, cyanoaralkyl group, nitro Aralkyl groups, hydroxyaralkyl groups, mercaptoaralkyl groups, acylaralkyl groups, heteroarylalkyl groups, lower alkylheteroarylalkyl groups,
Lower alkoxyheteroarylalkyl group, halogenated heteroarylalkyl group, cyanoheteroarylalkyl group, nitroheteroarylalkyl group, hydroxyheteroarylalkyl group, mercaptoheteroarylalkyl group or acylheteroarylalkyl group And the like. Among these, a lower alkyl group is more preferred.

In the present invention, the lower alkyl group is
A chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group , A pentyl group, a hexyl group and the like. The lower alkoxy group means a group in which an oxygen atom is bonded to the lower alkyl group, and specifically, for example, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group,
Examples thereof include an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group. More specifically, examples of the halogen atom include a chlorine atom, a bromine atom, and a fluorine atom.

Here, specific examples of the N-benzylpiperidinecarboxylic acid derivative (II) include, for example, the following compounds, but the present invention is not limited thereto. (1) Methyl N-benzyl-4-piperidinecarboxylate (2) Ethyl N-benzyl-4-piperidinecarboxylate (3) Propyl N-benzyl-4-piperidinecarboxylate (4) N-benzyl-4-piperidinecarboxylate Phenyl acid (5) benzyl N-benzyl-4-piperidinecarboxylate N-benzylpiperidinecarboxylic acid derivative (II)
It can be synthesized from pyridine carboxylic acid or the like, or can be obtained as a pharmaceutical raw material, reagent, industrial raw material, or the like.

Finally, N-benzyl-4-formylpiperidine (III) according to the present invention is a target compound of the present invention,
It is represented by the following chemical formula. [CAS Registry Number: 22065-85-6]

[0016]

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Next, the reaction method of the present invention will be described.
In the present invention, first, sodium bis (2-methoxyethoxy) aluminum hydride is reacted with cyclic amine (I) to prepare a reducing agent (Step 1). The present reducing agent is a novel compound and is useful in a reaction for reducing a carboxylic acid or ester to selectively obtain an aldehyde.

The amounts of the sodium bis (2-methoxyethoxy) aluminum hydride and the cyclic amine (I) are not limited. Usually, sodium bis (2-methoxyethoxy) aluminum hydride is converted to an N-benzylpiperidinecarboxylic acid derivative ( II) 1 equivalent or more, more preferably 1 to 3 equivalents or more, cyclic amine (I) hydrogenated bis (2-methoxyethoxy)
It is preferable to use 1 equivalent or more based on sodium aluminum.

The reducing agent prepared as described above has excellent reactivity and selectivity by itself. However, by further adding an alkali metal alcoholate (IV), the formation of by-products is suppressed, and the reducing agent is more efficiently used. The desired product can be obtained.

The alkali metal alcoholate (IV) according to the present invention is not limited as long as it is obtained by reacting an alkali metal with a lower alcohol or phenol having 1 to 6 carbon atoms. For example, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxyethoxide, sodium phenoxide and the like can be mentioned. Among these, potassium t-butoxide, sodium t-butoxide, sodium methoxyethoxide, and sodium phenoxide are more preferable.

The alkali metal alcoholate (IV) according to the present invention is available as reagents, industrial raw materials, etc.
It can also be produced from an alkali metal and a lower alcohol or phenol.

The amount of the alkali metal alcoholate (IV) to be used is also not limited, but is usually 0.01 to 0.3 equivalent, preferably 0.03 equivalent to the N-benzylpiperidinecarboxylic acid derivative (II).
〜0.25 equivalents, more preferably 0.05-0.2 equivalents are used.

In this reaction, a solvent may be used or not used, but is preferably used for the purpose of increasing the stirring efficiency and facilitating the control of the reaction temperature. The solvent that can be used is not limited as long as it is an inert solvent to bis (2-methoxyethoxy) aluminum sodium hydride, cyclic amine (I) or alkali metal alcoholate (IV), but usually benzene, toluene, Xylene,
Petroleum benzene, pentane, hexane, petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran (hereinafter, THF), dioxane, dioxolan, ethylene glycol dimethyl ether, etc. can be used, among which THF, t-butyl methyl Ethers are more preferred.

The amount of the solvent to be used is not limited, but usually 0.1 to 100 ml, more preferably 0.5 to 50 ml, and still more preferably 1 to 30 ml, per 1 g of the cyclic amine (I).

Although the reaction temperature is not limited, it is usually -78 ° C.
To room temperature, preferably -50 ° C to room temperature, more preferably -30
The temperature is selected from the range of C to room temperature.

The reaction time varies depending on the amount of the solvent used, the reaction temperature and the like, but is usually completed within several hours. The order of addition is not limited, and bis (2-methoxyethoxy) aluminum sodium hydride may be added to cyclic amine (I), or conversely, cyclic amine (I) may be hydrogenated bis (2-methoxyethoxy) It may be added to aluminum sodium. Also, when adding an alkali metal alcoholate (IV),
Alkali metal alcoholate (IV), sodium bis (2-methoxyethoxy) aluminum hydride and cyclic amine
The order of adding (I) is not limited. This reaction is carried out under a stream of an inert gas such as nitrogen, argon, etc.
Better results are obtained in the yield or purity of the desired product.

Subsequently, in the present invention, the N-benzylpiperidinecarboxylic acid derivative (II) is reduced using the above-mentioned novel reducing agent to give the desired N-benzyl-4-formylpiperidine.
(III) is obtained (Step 2). The temperature of this reaction is not limited, but is usually selected from the range of -78 ° C to room temperature, preferably -50 ° C to room temperature, more preferably -30 ° C to room temperature. The reaction time varies depending on the amount of the solvent used, the reaction temperature and the like, but is usually completed within several hours. The order of addition is not limited, and the reducing agent may be added to the N-benzylpiperidinecarboxylic acid derivative (II), or conversely, the N-benzylpiperidinecarboxylic acid derivative (II) may be added to the reducing agent. Good. In addition, better results can be obtained by carrying out this reaction under a stream of an inert gas such as nitrogen.

After completion of the reaction, the excess reducing agent is quenched with acetone or the like, and the insolubles are filtered off.
After concentrating to obtain a crude product, the reaction solution may be added to an aqueous alkali solution to decompose, and then extracted, washed with water, dried and concentrated. The crude product can be purified by a conventional method such as column chromatography or distillation, or has a purity that can be used without purification in the next step.

The following invention is disclosed in Japanese Patent Application Laid-Open No. 51-125,003. (1) An organic carboxylic acid or its reactive derivative at a carboxyl group is represented by the general formula LiAlHR ¹ R ² R ³ or the general formula AlHR ² R ³
A novel method for producing an aldehyde, characterized by reduction with a compound represented by the formula: (2) a compound represented by the general formula LiAlHR ¹ R ² R ³ or the general formula AlHR ² R ³ , wherein a secondary amine is reacted with lithium aluminum hydride or aluminum hydride in a molar ratio of about 1 to 3; Recipe. JP-A-51-125003 is also an invention relating to a method for obtaining an aldehyde from a carboxylic acid or ester, but the reducing agent is completely different from the present invention, and the N-benzyl according to the present invention
There is no disclosure of a specific example for obtaining -4-formylpiperidine (III).

Lithium aluminum hydride is highly ignitable as a single powder or pellet and corrosive to the skin, so that it has been difficult to handle it industrially. On the other hand, lithium aluminum hydride / tetrahydrofuran solution and the like have been developed and marketed in order to improve and improve the ignitability and handleability, but the problems in flammability and price have not been improved. In addition, lithium aluminum hydride is difficult to treat the reaction residue, and is not suitable as an industrial production method in this respect as well. Aluminum hydride is not commercially available due to its instability.It is necessary to prepare lithium hydride and aluminum chloride in ether when necessary. There are many problems such as generation and easy decomposition, flammability of ether, etc., and it was impossible to use industrially.

Further, the conditions of JP-A-51-125,003 are
For example, when applied to methyl N-benzyl-4-isonipecotate or ethyl N-benzyl-4-isonipecotate, good results were not actually obtained. (See Comparative Example 2)

Although the following document discloses the same invention as that of JP-A-51-125003, the reducing agent is completely different from that of the present invention, and N-benzyl-4-formylpiperidine (III) There are no application examples or references. (1) Chemistry Letters, 1447-1450, 1974. (2) Chemistry Letters, 215-218, 1975. (3) Chemistry Letters, 875-878, 1975. (4) Helv. Chim. Acta, 60 , 3025, 1977 (5) Org. React., 36 , 249, 1988.

Next, Japanese Patent Publication No. 50-28,404 (US Pat. No. 3,660,416) states that "at a temperature not exceeding 0 ° C., in an ether or aromatic hydrocarbon solvent, the general formula R ³ COOR ^4. the in represented by esters, formula NaAlHx (OR ⁸⁾ _4-x, wherein the reduction with sodium aluminum hydride represented by the general formula R ³ CHO preparation of aldehydes represented by ...... " Is disclosed. However, as in Comparative Example 3 described below, even if the method of JP-B-50-28,404 is applied to the N-benzylpiperidinecarboxylic acid derivative (II) according to the present invention, there are many by-products and the desired N-benzyl- The yield of 4-formylpiperidine (III) was low. As described above, it is apparent that the present invention has surprisingly superior effects as compared with the prior art.

Next, the present invention will be described in more detail with reference to the following examples. However, it goes without saying that the present invention is not limited to these examples.

EXAMPLES Example 1 N-benzyl-4-formylpiperidi
Synthesis

[0035]

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6.22 g (20 mmol) of a 65% sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution was dissolved in anhydrous THF (20 ml), and pyrrolidine 1.56 g (22 mmol) / anhydrous THF (6.5 ml) solution
It was added dropwise over 15 minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour to prepare a reducing reagent. 2.33 g (10 mmol) of methyl N-benzyl-4-isonipecotate were dissolved in anhydrous THF (20 ml),
While stirring this solution at −10 ° C. under a nitrogen stream, the above-mentioned reducing reagent was added dropwise over 30 minutes, and the reaction was further performed at the same temperature for 1 hour. Then, at -5 ° C, the reaction solution was added dropwise to a mixture of acetic acid (7.2 g) / acetone (10 ml) / water (10 ml) over 30 minutes. Precipitated white crystals were filtered off, and the crystalline portion was toluene (2
0 ml). The filtrate was concentrated under reduced pressure to give a pale yellow oil.
1.95 g was obtained. The pale yellow oil was purified using silica gel column chromatography (toluene / ethyl acetate system) to obtain 1.55 g of the title compound as a colorless oil. (Yield; 76.
6%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.63 (2H, dd, J = 4 Hz, 10
Hz), 1.84 (2H, dd, J = 4Hz, 12Hz), 2.06 (2H, dd, J = 4Hz, 12Hz),
2.24 (1H, m), 2.82 (2H, dd, J = 4Hz, 10Hz), 3.50 (2H, S), 7.28
(3H, S), 7.31 (2H, S), 9.62 (1H, S). IR; 2820, 2720, 1725 cm ^-1 . Mass; M + 203.

Examples 2 to 4 N-benzyl-4-formylpy
Synthesis of Peridine Instead of pyrrolidine in Example 1, N-methylpiperazine,
Using morpholine and piperidine under the same conditions and operation as in Example 1, the following results were obtained.

Examples 5 to 8 N-benzyl-4-formylpy
Synthesis of Peridine In place of methyl N-benzyl-4-isonipecotate in Example 1, 2.47 g of ethyl N-benzyl-4-isonipecotate (10%)
mmol) and pyrrolidine, N-methylpiperazine, morpholine, piperidine (20 mmol each) as the cyclic amine under the same conditions and operations as in Example 1 to obtain the following results.

Example 9 N-benzyl-4-formylpiperi
Synthesis of gin 65% -bis (2-methoxyethoxy) aluminum sodium hydride / 93.3 g (0.3 mol) of toluene solution in anhydrous THF (300 ml)
And a solution of pyrrolidine 21.3 g (0.3 mol) / anhydrous THF (100 ml) was added dropwise over 1 hour while stirring at −15 to −10 ° C. under a nitrogen stream. After completion of the dropwise addition, the mixture was stirred at -10 ° C for 1 hour,
A reducing reagent was prepared. 49.4 g (0.2 mol) of ethyl N-benzyl-4-isonipecotate was dissolved in anhydrous THF (200 ml), and the solution was added dropwise over 1.5 hours while stirring the solution at -15 ° C under a nitrogen stream. Then, the reaction was further performed at the same temperature for 1 hour. Then, at -5 ° C, the reaction solution was added dropwise to a mixture of a 2N aqueous solution of sodium hydroxide (200 ml) / methanol (200 ml) over 1 hour. The organic layer was separated, washed with water, and concentrated under reduced pressure to obtain 41.4 g of a yellow oil. This was dissolved in 5N hydrochloric acid (100 ml) and toluene (100 ml), and stirred at 0 to 5 ° C. for 2 hours.
And extracted with toluene (100 ml), washed with water,
Dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain 40.7 g of a pale yellow oil. This was subjected to precision distillation with a rectifying column, and the title compound was obtained as a colorless oil at a boiling point of 115 ° C / 0.3 mmHg.
30.4 g was obtained. (Yield: 74.9%) ¹ H-NMR, IR, and Mass data of the obtained product were consistent with the results of Example 1.

Examples 10 to 12 N-benzyl-4-formi
Synthesis of lupiperidine Instead of pyrrolidine in Example 9, N-methylpiperazine,
Using morpholine and piperidine under the same conditions and operations as in Example 9, the following results were obtained.

Example 13 N-benzyl-4-formylpipe
Synthesis of lysine (addition of potassium t-butoxide) 72.6 g (0.233 mol) of a 65% sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution was added to t-butyl methyl ether (hereinafter, MT
BE), and cooled to -25 ° C under a nitrogen stream. Here, a solution of 21.1 g (0.293 mol) of pyrrolidine / 51.4 g of MTBE was added to 2
It was dropped over time. After the addition was completed, the mixture was further stirred for 2 hours. Furthermore, potassium t-butoxide 1.85g (0.0164mol) /
8.1 g of THF solution was added and stirred for 1 hour to prepare a reducing reagent. Ethyl N-benzyl-4-isonipecotate 29.3 g (0.1
18 mol) was dissolved in 86.6 g of MTBE, and the above-mentioned reducing reagent was added dropwise thereto over 4 hours while stirring at about 10 ° C. under a nitrogen stream, followed by further stirring at room temperature for 1 hour. Under cooling, the reaction solution was added dropwise to a 4N aqueous solution of sodium hydroxide (187 ml). After stirring for 30 minutes, water (200 ml) was added, and the organic layer was separated. The organic layer
Wash, dry and concentrate under reduced pressure to give the title compound as a yellow oil (23.6 g)
I got (Yield: 97.8%, GLC purity: 96.0%)

Examples 14 to 19 N-benzyl-4-formi
Synthesis of Lupiperidine ( Addition of Alkali Metal Alcoholate (IV)) Under the same conditions and operation as in Example 13, alkali metal alcoholate (IV) was added under the following conditions, and the following results were obtained. * Molar ratio of alkali metal alcoholate (IV) to ethyl N-benzyl-4-isonipecotate

Production Example 1 N-benzyl-4-isonipecotin
Of Methyl Acid

[0044]

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Methyl isonicotinate 40 g (0.29 mol), 5%
8 g of rhodium / carbon catalyst (50% wet) in methanol (200 ml)
And subjected to catalytic reduction at 40 ° C. under a hydrogen pressure of 4 kg / cm ² for 4 hours using a medium-pressure reduction apparatus. After filtering the insoluble matter, the filtrate was concentrated under reduced pressure to obtain 39.7 g of colorless oily methyl isonipecotate.
(Yield; 94.7%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.44 (1 H, broad), 1.52
(2H, dd, J = 4Hz, 10Hz), 1.82 (2H, dd, J = 4Hz, 12Hz), 2.34 (1H.
m), 2.56 (2H, dd, J = 4Hz, 12Hz), 3.04 (2H, dd, J = 4Hz, 10Hz),
3.63 (3H, S).

27 g of the above methyl isonipecotate (0.188 mol
l), 15.9 g (0.19 mol) of sodium hydrogen carbonate, 23.9 g (0.19 mol) of benzyl chloride, acetone (70 ml), and water (70 ml) were mixed, and the mixture was stirred and refluxed at 70 ° C. for 3 hours. After cooling, the reaction solution was extracted by adding toluene (100 ml), washed with water, dried, and concentrated under reduced pressure to obtain 40.2 g of a crude product. This is distilled under reduced pressure and the boiling point
At 110 to 112 ° C / 0.1 mmHg, 38.8 g of the title compound was obtained as a colorless oil. (Yield; 88.6%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.66 (2H, dd, J = 4 Hz, 10
Hz), 1.77 (2H, dd, J = 4Hz, 12Hz), 1.94 (2H, dd, J = 4Hz, 12Hz),
2.22 (1H, m), 2.78 (2H, dd, J = 4Hz, 10Hz), 3.40 (2H, S), 3.58
(3H, S), 7.22 (3H, S), 7.28 (2H, S). Mass; M + 233.

Production Example 2 N-benzyl-4-isonipecotin
Of ethyl acrylate

[0048]

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236 g (1.5 mol) of ethyl isonipecotate,
136 g (1.5 mol) of sodium hydrogen carbonate, 190 g of benzyl chloride
(1.5 mol), ethanol (500 ml), water (500 ml),
The mixture was stirred and refluxed at ℃ for 3 hours. After cooling, the reaction solution was extracted by adding toluene (500 ml), washed with water, dried, and concentrated under reduced pressure to obtain 373 g of a crude product. This is distilled under reduced pressure and has a boiling point of 112 to 11.
At 5 ° C / 0.1 mmHg, 362 g of the title compound was obtained as a colorless oil.
(Yield; 97.7%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.22 (3 H, t, J = 14 Hz),
1.78 (2H, dd, J = 4Hz, 10Hz), 1.88 (2H, dd, J = 4Hz, 12Hz), 2.04
(2H, dd, J = 4Hz, 12Hz), 2.26 (1H, m), 2.86 (2H, dd, J = 4Hz, 10H
z), 3.48 (2H, s), 4.15 (2H, dd, J = 8Hz, 14Hz), 7.3 (3H, s), 7.5
(2H, s). Mass; M + 247.

Comparative Example 1 N-benzyl-4-formylpiperi
Synthesis of gin (reduction with sodium bis (2-methoxyethoxy) aluminum hydride modified with diethylamine) A solution of 3.11 g (10 mmol) of a 65% -sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution in anhydrous THF (12 ml) ), And stirred at −10 ° C. under a nitrogen gas stream while diethylamine 0.73 g
(10 mmol) / anhydrous THF (5 ml) solution was added dropwise over 15 minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes to prepare a reducing reagent.
1.24 g (5 mmol) of ethyl N-benzyl-4-isonipecotate was dissolved in anhydrous THF (20 ml), and the solution was added dropwise over 30 minutes while stirring the solution at -10 ° C under a nitrogen stream. The reaction was continued for another hour at the same temperature. When the reaction solution was checked by GLC, the production rate of the target aldehyde ^{* 1} was 36.6%, and the alcohol ^{* 2} whose reduction had progressed was produced at 46.5%, and the raw material ^{* 3} remained. ^{* 1} ; N-benzyl-4-formylpiperidine ^{* 2} ; N-benzyl-4-hydroxymethylpiperidine ^{* 3} ; Ethyl N-benzyl-4-isonipecotate

GLC conditions (see FIG. 1) カ ラ ム Column; DB-1 (0.25 μm, 0.25 mm × 30 m) Flow rate; 60 ml / min. Temperature ; 150-250 ℃ ───────────────────

Comparative Example 2 N-benzyl-4-formylpiperi
Synthesis of gin (reduction by the method of JP-A-51-125003) Lithium aluminum hydride (LiAlH ₄ ) was mixed with THF (50 ml) according to the following recipe.
And pyrrolidine / THF (10m
l) The solution was added dropwise and stirred for 1 hour. Here, at −20 ° C., 2.47 g (10 mmol) of ethyl N-benzyl-4-isonipecotate / THF
(10 ml) solution was added dropwise, and the reaction solution after 1 hour was checked under the above GLC conditions.

[0053] ^{* 1} ; N-benzyl-4-formylpiperidine ^{* 2} ; N-benzyl-4-hydroxymethylpiperidine ^{* 3} ; Ethyl N-benzyl-4-isonipecotinate ☆; 65% -bis (2-methoxyethoxy) aluminum hydride Sodium / toluene solution

As is clear from the above results, Japanese Patent Application Laid-Open No.
In the method of 25,003, the target product (aldehyde) is 78
%, And a large amount of alcohol was by-produced, resulting in poor reaction selectivity. On the other hand, when the amount of the reducing agent used was reduced, the reaction was not completed and alcohol was generated.

Comparative Example 3 N-benzyl-4-formylpiperi
Synthesis of gin (reduction by the method of JP-B-50-28,404)
A predetermined amount of a 5% -sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution was dissolved in anhydrous THF (20 ml), and N-benzyl-
Methyl 4-isonipecotate 2.33 g (10 mmol) / anhydrous THF (20
ml) solution was added dropwise over 30 minutes, and further reacted at the same temperature for 1 hour. Then, at −5 ° C., the reaction solution was treated with
(10 ml) / water (10 ml) was added dropwise over 30 minutes. The precipitated white crystals were separated by filtration, and the crystal portions were washed with toluene (20 ml). The filtrate was concentrated under reduced pressure to obtain a pale yellow oil.
The pale yellow oil was analyzed by GLC to determine the desired N-benzyl-4-formylpiperidine production ratio.

[0056] ☆; Sodium bis (2-methoxyethoxy) aluminum hydride ^{* 1} ; N-benzyl-4-formylpiperidine ^{* 2} ; N-benzyl-4-hydroxymethylpiperidine ^{* 3} ; Methyl N-benzyl-4-isonipecotate

As is apparent from the above results,
In the method of No. 8,404, although the reaction was carried out at an extremely low temperature of -50 ° C., only 80% of the target product was formed at the maximum, and the raw materials remained. Further, when the amount of the reducing agent used was further increased, although the raw materials were consumed, the production of alcohol increased, and conversely, the production ratio of the desired product decreased.

[Brief description of the drawings]

FIG. 1 is a GLC measurement chart in Comparative Example 1.

Claims (9)

[Claims] 1. An N-benzylpiperidine carboxylic acid derivative (II) represented by the following general formula using a reducing agent derived from sodium bis (2-methoxyethoxy) aluminum hydride and a cyclic amine (I). 1) (In the formula, R is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkynyl group which may be substituted, a lower cycloalkyl group which may be substituted, An aryl group which may be substituted, a heteroaryl group which may be substituted, an aralkyl group which may be substituted or a heteroarylalkyl group which may be substituted.) N-benzyl represented by the following chemical formula
-4- Formyl piperidine (III) production method. Embedded image 2. The method for producing N-benzyl-4-formylpiperidine (III) according to claim 1, wherein the cyclic amine (I) is at least one selected from pyrrolidine, piperidine, morpholine and N-methylpiperazine. 3. The method according to claim 1, wherein the cyclic amine (I) is used in an amount of 1 equivalent or more based on sodium bis (2-methoxyethoxy) aluminum hydride.
Method for producing benzyl-4-formylpiperidine (III). 4. The method for producing N-benzyl-4-formylpiperidine (III) according to claim 1, wherein R is a lower alkyl group. 5. The method according to claim 1, wherein the reducing agent derived from sodium bis (2-methoxyethoxy) aluminum hydride and the cyclic amine (I) further comprises an alkali metal alcoholate (IV). N-benzyl-4 as described
-Method for producing formylpiperidine (III). 6. The method according to claim 1, wherein the alkali metal alcoholate (IV) is one selected from potassium t-butoxide, sodium t-butoxide, sodium methoxyethoxide and sodium phenoxide. N-
Method for producing benzyl-4-formylpiperidine (III). 7. The amount of the alkali metal alcoholate (IV) used is based on the N-benzylpiperidinecarboxylic acid derivative (II).
The method for producing N-benzyl-4-formylpiperidine (III) according to any one of claims 1 to 6, which is 0.01 to 0.3 equivalent. 8. A reducing agent derived from a cyclic amine (I) and sodium bis (2-methoxyethoxy) aluminum hydride. 9. A reducing agent derived from a cyclic amine (I) and sodium bis (2-methoxyethoxy) aluminum hydride, further added with an alkali metal alcoholate (IV).